20-54154057-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000782.5(CYP24A1):c.*715C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 151,540 control chromosomes in the GnomAD database, including 5,759 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: CYP24A1 NM_000782.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.836

Genes affected

CYP24A1 (HGNC:2602): (cytochrome P450 family 24 subfamily A member 1) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein initiates the degradation of 1,25-dihydroxyvitamin D3, the physiologically active form of vitamin D3, by hydroxylation of the side chain. In regulating the level of vitamin D3, this enzyme plays a role in calcium homeostasis and the vitamin D endocrine system. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 20-54154057-G-C is Benign according to our data. Variant chr20-54154057-G-C is described in ClinVar as [Benign]. Clinvar id is 338797.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-54154057-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.314 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP24A1	NM_000782.5	c.*715C>G		3_prime_UTR_variant	12/12	ENST00000216862.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP24A1	ENST00000216862.8	c.*715C>G		3_prime_UTR_variant	12/12	1	NM_000782.5	P1
CYP24A1	ENST00000395955.7	c.*715C>G		3_prime_UTR_variant	11/11	1

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39884 AN: 151416 Hom.: 5753 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.326

Gnomad FIN AF: 0.387

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.263 AC: 39928 AN: 151536 Hom.: 5759 Cov.: 32 AF XY: 0.268 AC XY: 19816 AN XY: 74014

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.224

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.327

Gnomad4 FIN AF: 0.387

Gnomad4 NFE AF: 0.317

Gnomad4 OTH AF: 0.268

Alfa AF: 0.180 Hom.: 390

Bravo AF: 0.241

Asia WGS AF: 0.236 AC: 823 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercalcemia, infantile, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.15
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6022987; hg19: chr20-52770596;